The proinflammatory cytokine interleukin (IL)-1β plays a pivotal role in the behavioral manifestations (i.e., sickness) of the stress response. Indeed, exposure to acute and chronic stressors induces the expression of IL-1β in stress-sensitive brain regions. Thus, it is typically presumed that exposure to stressors induces the extra-cellular release of IL-1β in the brain parenchyma. However, this stress-evoked neuroimmune phenomenon has not been directly demonstrated nor has the cellular process of IL-1β release into the extracellular milieu been characterized in brain. This cellular process involves a form of inflammatory cell death, termed pyroptosis, which involves: 1) activation of caspase-1, 2) caspase-1 maturation of IL-1β, 3) caspase-1 cleavage of gasdermin D (GSDMD), and 4) GSDMD-induced permeability of the cell membrane through which IL-1β is released into the extracellular space. Thus, the present study examined whether stress induces the extra-cellular release of IL-1β and engages the above cellular process in mediating IL-1β release in the brain. Male Sprague-Dawley rats were exposed to inescapable tailshock (IS). IL-1β extra-cellular release, caspase-1 activity and cleavage of GSDMD were measured in dorsal hippocampus. We found that exposure to IS induced a transient increase in the release of IL-1β into the extracellular space immediately after termination of the stressor. IS also induced a transient increase in caspase-1 activity prior to IL-1β release, while activation of GSDMD was observed immediately after termination of the stressor. IS also increased mRNA and protein expression of the ESCRTIII protein CHMP4B, which is involved in cellular repair. The present results suggest that exposure to an acute stressor induces the hallmarks of pyroptosis in brain, which might serve as a key cellular process involved in the release of IL-1β into the extracellular milieu of the brain parenchyma.

中文翻译：

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急性应激诱导背侧海马中 caspase-1、gasdermin D 和组成型 IL-1β 蛋白的快速和瞬时诱导

促炎细胞因子白细胞介素 (IL)-1β 在应激反应的行为表现（即疾病）中起关键作用。事实上，暴露于急性和慢性压力源会诱导 IL-1β 在压力敏感的大脑区域中的表达。因此，通常假设暴露于压力源会诱导脑实质中 IL-1β 的细胞外释放。然而，这种压力诱发的神经免疫现象尚未得到直接证实，也没有在大脑中表征 IL-1β 释放到细胞外环境中的细胞过程。这种细胞过程涉及一种称为细胞焦亡的炎症细胞死亡形式，包括：1) caspase-1 的激活，2) IL-1β 的 caspase-1 成熟，3) gasdermin D (GSDMD) 的 caspase-1 裂解，和 4) GSDMD 诱导的细胞膜通透性，IL-1β 通过该通透性释放到细胞外空间。因此，本研究检查了压力是否会诱导 IL-1β 的细胞外释放并参与上述细胞过程来介导大脑中的 IL-1β 释放。雄性 Sprague-Dawley 大鼠暴露于不可避免的尾震 (IS)。在背侧海马中测量 IL-1β 细胞外释放、caspase-1 活性和 GSDMD 的裂解。我们发现暴露于 IS 会在压力源终止后立即诱导 IL-1β 释放到细胞外空间的瞬时增加。IS 还在 IL-1β 释放之前诱导了 caspase-1 活性的瞬时增加，而在压力源终止后立即观察到 GSDMD 的激活。IS 还增加了参与细胞修复的 ESCRTIIII 蛋白 CHMP4B 的 mRNA 和蛋白质表达。目前的结果表明，暴露于急性压力源会诱导大脑中细胞焦亡的特征，这可能是参与 IL-1β 释放到脑实质细胞外环境的关键细胞过程。